Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor.

PURPOSE: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors. EXPERIMENTAL DESIGN: Patients (n=73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of >6 months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC). RESULTS: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus -0.01 CEC/microL/d, P=0.03) and smaller decreases in monocyte levels (47% versus 60%, P=0.007) during cycle 1. VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes, VEGF, and sVEGFR-2 all rebounded towards baseline off treatment. CONCLUSIONS: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.     

The Malawi National Tuberculosis Programme: an equity analysis

Background  

Until 2005, the Malawi National Tuberculosis Control Programme had been implemented as a vertical programme. Working within the Sector Wide Approach (SWAp) provides a new environment and new opportunities for monitoring the equity performance of the programme. This paper synthesizes what is known on equity and TB in Malawi and highlights areas for further action and advocacy.     

Mycoplasmas among clients attending a family planning clinic in Zaria, Nigeria

The effect of contraception in the incidence of genital tract mycoplasma infection was studied in 150 women practicing contraception and another 50 women attending a gynecological clinic, using no contraception. Using the chi-squared method, there was no statistically significant difference between total mycoplasma recovery in family planning clients versus the controls. The only statistically significant difference was between total positive mycoplasma in the oral contraceptive group versus IUD users.     

Secretory IgA and other proteins in semen from healthy Nigerian men

The secretory IgA (SIgA) levels in semen and immunoglobulin A, G, M and D concentrations in semen and serum from 30 apparently healthy Nigerian men with various sperm counts were studied. Albumin levels in the samples were also measured to determine the contribution of serum transudation to the semen concentration. Nine of the participants (30%) had no detectable SIgA in their semen, while IgM and IgD were undetectable in all the semen samples. Analysis of proteins in the semen revealed an increase in the IgA:albumin ratio as compared to serum, while the IgG:albumin ratio was the same. The relative semen concentrations for IgA were generally slightly higher than and for IgG were lower than for albumin. Those levels did not correlate for IgA and albumin, while the IgG and albumin levels correlated with each other. A mathematical estimate of the amount of IgA produced locally showed no statistically significant difference between azoospermic and normospermic men. The data indicate that some men are capable of local IgG production.     

A pharmacological study of Araujia sericifera B. extracts in rodents

The present study analyses the pharmacological activity in in vitro and in vivo models of different extracts obtained from Araujia sericifera. The hexane extract of fruits lacked toxicity, but exhibited an analgesic effect in models of chemical and thermal stimulation. Such an extract was the only one which exhibited antiinflammatory actions. The intrinsic effect on arterial blood pressure was biphasic: at low doses it significantly increased blood pressure, whereas at high doses it exerted the opposite effect. On isolated organs it produced a marked decrease in the maximum effect of histamine and acetylcholine. The dichloromethanol extract of fruits decreased arterial pressure and the maximum effect of histamine. The methanol extract of fruits slightly depressed the CNS. An analgesic effect was noted following chemical stimulation; the maximum effect of serotonin was significantly decreased. The dichloromethanol extract of seeds markedly decreased arterial pressure and the maximum effect of acetylcholine and serotonin. The methanol extract of seeds exerted an analgesic effect after chemical stimulation and modified the maximum effect of noradrenaline and serotonin.     

Pharmacological evaluation of the dichloromethanol extract from Inula crithmoides L.

The pharmacological effect of the dichloromethanol extract of Inula crithmoides L. was analysed in in vitro and in vivo models. The extract dose-dependently decreased arterial blood pressure and furthermore it showed low acute toxicity, CNS depressor activity and analgesic and antiinflammatory effects. Preincubation of the guineapig ileum and rat duodenum (100 μg/mL) produced a significant reduction in the contractile effects of histamine and acetylcholine and a concentration-related inhibition of the effects of serotonin. Following further fractionation the methylene chloride/acetone (50/50) fraction caused a significant decrease in motor activity and significantly reduced the threshold of pain chemical stimulus.     

Homologous recombinational repair vis-à-vis chlorambucil resistance in chronic lymphocytic leukemia

The objective of this study was to further define the role of homologous recombinational repair (HRR) in resistance to the nitrogen mustards in B-cell chronic lymphocytic leukemia (B-CLL). We have demonstrated previously that increased chlorambucil (CLB)-induced HsRad51 nuclear foci formation correlated with a CLB-resistant phenotype in B-CLL lymphocytes. In this report, we measured the protein levels of HsRad51 and Xrcc3 (an HsRad51 paralog) and correlated them with the in vitro CLB cytotoxicity (LD(50)) in lymphocytes from seventeen B-CLL patients. Both HsRad51 (r=0.75, P=0.0005) and Xrcc3 (r=0.52, P=0.03) protein levels correlated with the in vitro CLB LD(50). In addition, multiple linear regression analysis showed a significant correlation between Xrcc3 and Rad51 protein levels versus the CLB LD(50) (r=0.78, P=0.0014), suggesting that both proteins influence CLB cytotoxicity. Moreover, since HsRad51 expression varies in cell lines during the cell cycle, we determined proliferating cell nuclear antigen (PCNA) protein levels to assess possible differences in cell cycle progression. There was no correlation between PCNA protein levels and the CLB LD(50) (r=0.042, P=0.87) or with HsRad51/Xrcc3 protein levels. Our data suggest that HsRad51 and Xrcc3 protein expression may be predictive of the response in B-CLL patients to treatment with nitrogen mustards.     

Evidence of otospongiosis obtained by computerized tomography. Does it compromise the post-stapedectomy auditory gain?

To study the influence of tomographic otospongiosis/otosclerosis on the audiometric gain after stapedectomy, we evaluated 34 patients (mean age 39.9 years, S.D. 9.8) with otosclerosis and mixed hearing loss. We performed Computed Tomography (CT) with densitometry before stapedectomy and audiometry before and 4 weeks after the surgery. CT results were classified as compatible or not for otospongiosis (< 1000 UH) or for otosclerosis (> 2000 UH). According to the affected turns of the cochlea, the studies were classified in 3 groups. In 43% of the patients the CT showed otospongiosis. After stapedectomy, air conduction thresholds of the low (125-500 Hz), middle (500-2000 Hz) and high frequency bands (2000-8000 Hz) and for the air/bone gap were similar for the ears with or without otospongiosis (p > 0.05, ANOVA). However, patients with otospongiosis in all the cochlea showed the lowest audiometric gain for the high frequency band (p < 0.05 ANOVA). Evidence of otospongiosis evaluated just by CT has a low impact on the audiometric outcome after stapedectomy.